The neurochemical and cellular mechanisms that contribute to the control of ethanol drinking behavior are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, e.g., the opiate peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opiate receptor antagonist, but its mechanism is not known in detail. Mu opiate receptors are anatomically located in the ventral tegmental area (VTA) and are known to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opiate receptor subtypes has not been firmly established. Our preliminary studies show that mu opiate receptors are involved in the mechanism by which ethanol stimulates dopamine release in the ventral striatum, one of the terminal areas of the mesolimbic system. We propose to determine whether genetic deletion or irreversible blockade of the mu opiate receptor alters the dose-response curve for ethanol-stimulated dopamine release in the ventral striatum (aim 1). The genetic model we propose to use will be congenic mu receptor knockouts and wild-type controls that have been established on a C57BL/6 background. These studies will be complemented by investigation of effects of irreversible blockade of mu receptors with the use of naloxonazine. We also will determine whether the deletion of the mu receptor or irreversible blockade alters ethanol consumption using a two bottle choice procedure (aim 2). Moreover, we propose to determine whether mu receptors in the ventral tegmental area or the ventral striatum are involved in the inhibitory effects of loss of mu receptor function on ethanol stimulated dopamine release (aim 3). This will be done by microinjection of naloxonazine into either area and measuring the ethanol response. The role of mu receptors in the control of VTA-dopamine neurons will be examined using electrophysiological measures of cellular and synaptic activity in GABAergic interneurons (aim 4). These studies will utilize both the genetic and pharmacological approaches as described above. Together, the proposed experiments will elucidate the role of mu opiate receptors in the modulation of mesolimbic dopamine activity by ethanol.